Background: Global intake of inorganic phosphate (Pi), primarily from processed foods, has risen markedly, and its systemic metabolic effects beyond mineral homeostasis remain poorly understood. Epidemiologic data paradoxically link higher Pi intake with lower BMI and reduced metabolic syndrome risk. The mechanisms underlying this association are unknown. Aim: To determine how dietary Pi regulates whole-body energy metabolism, adipose tissue remodeling, and endocrine stress responses, with emphasis on the FGF21/GDF15 mitohormetic axis.

C57BL/6J mice were fed normal chow, high-fat diet (HF), or diets enriched with moderate (HPi, 1.2%) or high (HHPi, 2.1%) Pi for 8-10 weeks. Metabolic phenotyping included body weight, glucose and insulin tolerance, indirect calorimetry, histology, ELISA, Western blotting, and qPCR. Pi actions in adipocytes were examined using differentiated 3T3-L1 and brown adipocytes, mitochondrial respiration, and thermogenic markers.

HPi markedly suppressed HF-induced weight gain, reduced fat mass, and improved insulin sensitivity. Pi supplementation increased oxygen consumption and heat production, accompanied by robust browning of white adipose tissue with upregulation of UCP1, PGC1α, and mitochondrial OXPHOS proteins. Hepatic and circulating FGF21 and GDF15 were significantly elevated, indicating activation of systemic mitohormesis. In vitro, high extracellular Pi rapidly increased mitochondrial ROS, induced FGF21/GDF15, and enhanced mitochondrial biogenesis and respiration in adipocytes. Recombinant FGF21 reiterated Pi-induced mitochondrial remodeling. Despite metabolic benefits, chronic Pi overload aggravated renal fibrosis.

Dietary phosphate acts as a previously unrecognized metabolic signal that stimulates FGF21/GDF15-dependent mitohormesis, inducing adipose browning, increased energy expenditure, and improved insulin sensitivity. These findings reveal phosphate as a double-edged nutrient with potent anti-obesity properties but potential renal risks. Understanding Pi-induced endocrine stress pathways may uncover novel therapeutic targets for obesity and metabolic disease.